Suppression of Nonsense Mutations by New Emerging Technologies
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Bio 102 Practice Problems Genetic Code and Mutation
Bio 102 Practice Problems Genetic Code and Mutation Multiple choice: Unless otherwise directed, circle the one best answer: 1. Choose the one best answer: Beadle and Tatum mutagenized Neurospora to find strains that required arginine to live. Based on the classification of their mutants, they concluded that: A. one gene corresponds to one protein. B. DNA is the genetic material. C. "inborn errors of metabolism" were responsible for many diseases. D. DNA replication is semi-conservative. E. protein cannot be the genetic material. 2. Choose the one best answer. Which one of the following is NOT part of the definition of a gene? A. A physical unit of heredity B. Encodes a protein C. Segement of a chromosome D. Responsible for an inherited characteristic E. May be linked to other genes 3. A mutation converts an AGA codon to a TGA codon (in DNA). This mutation is a: A. Termination mutation B. Missense mutation C. Frameshift mutation D. Nonsense mutation E. Non-coding mutation 4. Beadle and Tatum performed a series of complex experiments that led to the idea that one gene encodes one enzyme. Which one of the following statements does not describe their experiments? A. They deduced the metabolic pathway for the synthesis of an amino acid. B. Many different auxotrophic mutants of Neurospora were isolated. C. Cells unable to make arginine cannot survive on minimal media. D. Some mutant cells could survive on minimal media if they were provided with citrulline or ornithine. E. Homogentisic acid accumulates and is excreted in the urine of diseased individuals. 5. -
Truncating Mutations in Severe Intellectual Disability
European Journal of Human Genetics (2014) 22, 289–292 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg SHORT REPORT Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability Frederic Tran Mau-Them1, Marjolaine Willems*,1, Beate Albrecht2, Elodie Sanchez1, Jacques Puechberty1, Sabine Endele3, Anouck Schneider4, Nathalie Ruiz Pallares4,5, Chantal Missirian6, Francois Rivier7, Manon Girard4, Muriel Holder8, Sylvie Manouvrier8, Isabelle Touitou5, Genevieve Lefort4, Pierre Sarda1, Anne Moncla7, Severine Drunat9, Dagmar Wieczorek2 and David Genevieve1 Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C. European Journal of Human Genetics (2014) 22, 289–292; doi:10.1038/ejhg.2013.113; published online 15 May 2013 Keywords: syndromic X-linked intellectual disability; microcephaly; IQSEC2-truncating mutations INTRODUCTION native to the south of France. Pregnancy was uneventful. The boy was born at Intellectual disability (ID) is defined by substantial limitations in 37 ½ weeks of gestation full term by caesarean section due to an abnormal cognitive functioning (intellectual quotient o70) coupled with a deficit presentation. -
Expanding the Genetic Code Lei Wang and Peter G
Reviews P. G. Schultz and L. Wang Protein Science Expanding the Genetic Code Lei Wang and Peter G. Schultz* Keywords: amino acids · genetic code · protein chemistry Angewandte Chemie 34 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200460627 Angew. Chem. Int. Ed. 2005, 44,34–66 Angewandte Protein Science Chemie Although chemists can synthesize virtually any small organic molecule, our From the Contents ability to rationally manipulate the structures of proteins is quite limited, despite their involvement in virtually every life process. For most proteins, 1. Introduction 35 modifications are largely restricted to substitutions among the common 20 2. Chemical Approaches 35 amino acids. Herein we describe recent advances that make it possible to add new building blocks to the genetic codes of both prokaryotic and 3. In Vitro Biosynthetic eukaryotic organisms. Over 30 novel amino acids have been genetically Approaches to Protein encoded in response to unique triplet and quadruplet codons including Mutagenesis 39 fluorescent, photoreactive, and redox-active amino acids, glycosylated 4. In Vivo Protein amino acids, and amino acids with keto, azido, acetylenic, and heavy-atom- Mutagenesis 43 containing side chains. By removing the limitations imposed by the existing 20 amino acid code, it should be possible to generate proteins and perhaps 5. An Expanded Code 46 entire organisms with new or enhanced properties. 6. Outlook 61 1. Introduction The genetic codes of all known organisms specify the same functional roles to amino acid residues in proteins. Selectivity 20 amino acid building blocks. These building blocks contain a depends on the number and reactivity (dependent on both limited number of functional groups including carboxylic steric and electronic factors) of a particular amino acid side acids and amides, a thiol and thiol ether, alcohols, basic chain. -
Variegate Porphyria: Identification of a Nonsense Mutation in The
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector MUTATION REPORTS Variegate Porphyria: Identification of a Nonsense Mutation in the Protoporphyrinogen Oxidase Gene Jorge Frank, Frank K. Jugert,* Katrin Kalka,† Gu¨nter Goerz,† Hans F. Merk,* and Angela M. Christiano Department of Dermatology, Columbia University, New York, New York, U.S.A.; *Department of Dermatology, University Clinic of the RWTH, Aachen, Germany; †Department of Dermatology, Heinrich Heine University, Du¨sseldorf, Germany The porphyrias are disorders of porphyrin metabolism protoporphyrinogen oxidase gene, resulting in the substi- that result from inherited or acquired aberrations in the tution of glutamic acid by a nonsense codon, designated control of the heme biosynthetic pathway. Variegate E133X. Our investigation establishes that a nonsense porphyria is characterized by a partial reduction in the mutation in the protoporphyrinogen oxidase gene is activity of protoporphyrinogen oxidase. In this study, we the underlying mutation in this family with variegate identified the first nonsense mutation in a family with porphyria. Key words: bullous diseases/genodermatosis/photo- variegate porphyria. The mutation consisted of a previ- sensitivity/porphyrin-heme biosynthetic pathway. J Invest ously unreported G-to-T transversion in exon 5 of the Dermatol 110:449–451, 1998 he porphyrias are disorders of heme metabolism resulting in the PPO gene in the clinically affected patient and one of her sons from the inherited or acquired dysregulation of one of by heteroduplex analysis, automated sequencing, and allele specific the eight enzymes that control the porphyrin-heme oligonucleotide (ASO) hybridization. The mutation consisted of a biosynthetic pathway. -
Excess of Rare Novel Loss-Of-Function Variants in Synaptic Genes in Schizophrenia and Autism Spectrum Disorders
Molecular Psychiatry (2014) 19, 872–879 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders EM Kenny1,3, P Cormican1,3, S Furlong1,3, E Heron1, G Kenny1, C Fahey1, E Kelleher1, S Ennis2, D Tropea1, R Anney1, AP Corvin1, G Donohoe1, L Gallagher1, M Gill1 and DW Morris1 Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P ¼ 0.02). This effect was stronger when analysis was limited to singleton LoF variants (P ¼ 0.0007) and the excess was present in both SZ (P ¼ 0.002) and ASD (P ¼ 0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P ¼ 0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. -
Quality Control of Eukaryotic Mrna: Safeguarding Cells from Abnormal Mrna Function
Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function Olaf Isken and Lynne E. Maquat1 Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA Cells routinely make mistakes. Some mistakes are en- (Dreyfuss et al. 2002). RNA-associated proteins not only coded by the genome and may manifest as inherited or reflect the history of the RNA but may also influence acquired diseases. Other mistakes occur because meta- future steps of RNA metabolism (Giorgi and Moore bolic processes can be intrinsically inefficient or inaccu- 2007). rate. Consequently, cells have developed mechanisms to Cells have evolved pathways to eliminate RNAs that minimize the damage that would result if mistakes went are incorrectly processed or improperly function either unchecked. Here, we provide an overview of three qual- because of mutations within the genes that encode them ity control mechanisms—nonsense-mediated mRNA de- or because of mistakes made during their metabolism cay, nonstop mRNA decay, and no-go mRNA decay. and/or function in the absence of mutations within their Each surveys mRNAs during translation and degrades genes. This review will focus on pathways that eliminate those mRNAs that direct aberrant protein synthesis. defective mRNAs as a consequence of their inability to Along with other types of quality control that occur dur- properly direct protein synthesis. These pathways en- ing the complex processes of mRNA biogenesis, these compass the translation-dependent mechanisms of mRNA surveillance mechanisms help to ensure the in- cytoplasmic surveillance. -
Translational Control Using an Expanded Genetic Code
Review Translational Control using an Expanded Genetic Code Yusuke Kato Division of Biotechnology, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization (NARO), Oowashi 1-2, Tsukuba, Ibaraki 305-8634, Japan; [email protected]; Tel.: +81-29-838-6059 Received: 19 December 2018; Accepted: 15 February 2019; Published: 18 February 2019 Abstract: A bio-orthogonal and unnatural substance, such as an unnatural amino acid (Uaa), is an ideal regulator to control target gene expression in a synthetic gene circuit. Genetic code expansion technology has achieved Uaa incorporation into ribosomal synthesized proteins in vivo at specific sites designated by UAG stop codons. This site-specific Uaa incorporation can be used as a controller of target gene expression at the translational level by conditional read-through of internal UAG stop codons. Recent advances in optimization of site-specific Uaa incorporation for translational regulation have enabled more precise control over a wide range of novel important applications, such as Uaa-auxotrophy-based biological containment, live-attenuated vaccine, and high-yield zero-leakage expression systems, in which Uaa translational control is exclusively used as an essential genetic element. This review summarizes the history and recent advance of the translational control by conditional stop codon read-through, especially focusing on the methods using the site-specific Uaa incorporation. Keywords: genetic switch; synthetic biology; unnatural amino acids; translational regulation; biological containment; stop codon read-through 1. Introduction Conditional induction of gene expression is one of the most important technologies for constructing synthetic gene circuits, and such regulation has applications from basic research to industrial use. -
Genome-Wide Transcriptional Sequencing Identifies Novel Mutations in Metabolic Genes in Human Hepatocellular Carcinoma DAOUD M
CANCER GENOMICS & PROTEOMICS 11 : 1-12 (2014) Genome-wide Transcriptional Sequencing Identifies Novel Mutations in Metabolic Genes in Human Hepatocellular Carcinoma DAOUD M. MEERZAMAN 1,2 , CHUNHUA YAN 1, QING-RONG CHEN 1, MICHAEL N. EDMONSON 1, CARL F. SCHAEFER 1, ROBERT J. CLIFFORD 2, BARBARA K. DUNN 3, LI DONG 2, RICHARD P. FINNEY 1, CONSTANCE M. CULTRARO 2, YING HU1, ZHIHUI YANG 2, CU V. NGUYEN 1, JENNY M. KELLEY 2, SHUANG CAI 2, HONGEN ZHANG 2, JINGHUI ZHANG 1,4 , REBECCA WILSON 2, LAUREN MESSMER 2, YOUNG-HWA CHUNG 5, JEONG A. KIM 5, NEUNG HWA PARK 6, MYUNG-SOO LYU 6, IL HAN SONG 7, GEORGE KOMATSOULIS 1 and KENNETH H. BUETOW 1,2 1Center for Bioinformatics and Information Technology, National Cancer Institute, Rockville, MD, U.S.A.; 2Laboratory of Population Genetics, National Cancer Institute, National Cancer Institute, Bethesda, MD, U.S.A.; 3Basic Prevention Science Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, U.S.A; 4Department of Biotechnology/Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, U.S.A.; 5Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 6Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea; 7Department of Internal Medicine, College of Medicine, Dankook University, Cheon-An, Korea Abstract . We report on next-generation transcriptome Worldwide, liver cancer is the fifth most common cancer and sequencing results of three human hepatocellular carcinoma the third most common cause of cancer-related mortality (1). tumor/tumor-adjacent pairs. -
Nonsense and Missense Mutations in Hemophilia A: Estimate of the Relative Mutation Rate at CG Dinucleotides Hagop Youssoufian,* Stylianos E
Am. J. Hum. Genet. 42:718-725, 1988 Nonsense and Missense Mutations in Hemophilia A: Estimate of the Relative Mutation Rate at CG Dinucleotides Hagop Youssoufian,* Stylianos E. Antonarakis,* William Bell,t Anne M. Griffin,4 and Haig H. Kazazian, Jr.* *Genetics Unit, Department of Pediatrics, and tDivision of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore; and tDivision of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill Summary Hemophilia A is an X-linked disease of coagulation caused by deficiency of factor VIII. Using cloned cDNA and synthetic oligonucleotide probes, we have now screened 240 patients and found CG-to-TG transitions in an exon in nine. We have previously reported four of these patients; and here we report the remaining five, all of whom were severely affected. In one patient a TaqI site was lost in exon 23, and in the other four it was lost in exon 24. The novel exon 23 mutation is a CG-to-TG substitution at the codon for amino acid residue 2166, producing a nonsense codon in place of the normal codon for arginine. Simi- larly, the exon 24 mutations are also generated by CG-to-TG transitions, either on the sense strand produc- ing nonsense mutations or on the antisense strand producing missense mutations (Arg to Gln) at position 2228. The novel missense mutations are the first such mutations observed in association with severe hemo- philia A. These results provide further evidence that recurrent mutations are not uncommon in hemophilia A, and they also allow us to estimate that the extent of hypermutability of CG dinucleotides is 10-20 times greater than the average mutation rate for hemophilia A. -
A Upf3b-Mutant Mouse Model with Behavioral and Neurogenesis Defects
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Mol Psychiatry Manuscript Author . Author Manuscript Author manuscript; available in PMC 2018 September 27. Published in final edited form as: Mol Psychiatry. 2018 August ; 23(8): 1773–1786. doi:10.1038/mp.2017.173. A Upf3b-mutant mouse model with behavioral and neurogenesis defects L Huang1, EY Shum1, SH Jones1, C-H Lou1, J Dumdie1, H Kim1, AJ Roberts2, LA Jolly3,4, J Espinoza1, DM Skarbrevik1, MH Phan1, H Cook-Andersen1, NR Swerdlow5, J Gecz3,4, and MF Wilkinson1,6 1Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA 2Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, MB6, La Jolla, CA 92037, USA 3School Adelaide Medical School and Robison Research Institute, University of Adelaide, Adelaide, SA 5005, Australia 4South Australian Health and Medical Research Institute, Adelaide, SA, 5005, Australia 5Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California, USA 6Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA Abstract Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ). -
Cancer Genomics Terminology
Cancer Genomics Terminology Acquired Susceptibility Mutation: A mutation in a gene that occurs after birth from a carcinogenic insult. Allele: One of the variant forms of a gene. Different alleles may produce variation in inherited characteristics. Allele Heterogeneity: A phenotype that can be produced by different genetic mechanisms. Amino Acid: The building blocks of protein, for which DNA carries the genetic code. Analytical Sensitivity: The proportion of positive test results correctly reported by the laboratory among samples with a mutation(s) that the laboratory’s test is designed to detect. Analytic Specificity: The proportion of negative test results correctly reported among samples when no detectable mutation is present. Analytic Validity: A test’s ability to accurately and reliably measure the genotype of interest. Apoptosis: Programmed cell death. Ashkenazi: Individuals of Eastern European Jewish ancestry/decent (For example-Germany and Poland). Non-assortative mating occurred in this population. Association: When significant differences in allele frequencies are found between a disease and control population, the disease and allele are said to be in association. Assortative Mating: In population genetics, selective mating in a population between individuals that are genetically related or have similar characteristics. Autosome: Any chromosome other than a sex chromosome. Humans have 22 pairs numbered 1-22. Base Excision Repair Gene: The gene responsible for the removal of a damaged base and replacing it with the correct nucleotide. Base Pair: Two bases, which form a “rung on the DNA ladder”. Bases are the “letters” (Adenine, Thymine, Cytosine, Guanine) that spell out the genetic code. Normally adenine pairs with thymine and cytosine pairs with guanine. -
A Protein with Similarities to Caenorhabditis Elegans SMG5 and SMG7 That Functions in the Dephosphorylation of Upf1
Downloaded from rnajournal.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Characterization of human Smg5/7a: A protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1 SHANG-YI CHIU,1 GUILLAUME SERIN,1,3 OSAMU OHARA,2 and LYNNE E. MAQUAT1 1Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA 2Department of Human Gene Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0812, Japan; Immunogenomics Research Team, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan ABSTRACT Nonsense-mediated mRNA decay (NMD) in mammalian cells depends on phosphorylation of Upf1, an RNA-dependent ATPase and 5-to-3 helicase. Upf1 phosphorylation is mediated by Smg1, a phosphoinositol 3-kinase–related protein kinase. Here, we describe a human protein, which we call hSmg5/7a, that manifests similarity to Caenorhabditis elegans NMD factors CeSMG5 and CeSMG7, as well as two Drosophila melanogaster proteins that are also similar to the C. elegans NMD factors. Results indicate that hSmg5/7a functions in the dephosphorylation of Upf1. Furthermore, hSmg5/7a copurifies with Upf1, Upf2, Upf3X, Smg1, and the catalytic subunit of protein phosphatase 2A. We also demonstrate that Upf2, another factor involved in NMD, is a phosphoprotein. However, hSmg5/7a plays no role in the dephosphorylation of Upf2. These data indicate that hSmg5/7a targets protein phosphatase 2A to Upf1 but not