DOCSLIB.ORG

Biallelic VARS Variants Cause Developmental Encephalopathy with Microcephaly That Is Recapitulated in Vars Knockout Zebrafish

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biallelic VARS Variants Cause Developmental Encephalopathy with Microcephaly That Is Recapitulated in Vars Knockout Zebrafish University of Southern Denmark Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish Siekierska, Aleksandra; Stamberger, Hannah; Deconinck, Tine; Oprescu, Stephanie N.; Partoens, Michèle; Zhang, Yifan; Sourbron, Jo; Adriaenssens, Elias; Mullen, Patrick; Wiencek, Patrick; Hardies, Katia; Lee, Jeong Soo; Giong, Hoi Khoanh; Distelmaier, Felix; Elpeleg, Orly; Helbig, Katherine L.; Hersh, Joseph; Isikay, Sedat; Jordan, Elizabeth; Karaca, Ender; Kecskes, Angela; Lupski, James R.; Kovacs-Nagy, Reka; May, Patrick; Narayanan, Vinodh; Pendziwiat, Manuela; Ramsey, Keri; Rangasamy, Sampathkumar; Shinde, Deepali N.; Spiegel, Ronen; Timmerman, Vincent; von Spiczak, Sarah; Helbig, Ingo; C4RCD Research Group; Møller, Rikke S.; Hjalgrim, Helle; AR working group of the EuroEPINOMICS RES Consortium; Weckhuysen, Sarah; Francklyn, Christopher; Antonellis, Anthony; de Witte, Peter A M; De Jonghe, Peter Published in: Nature Communications DOI: 10.1038/s41467-018-07953-w Publication date: 2019 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Siekierska, A., Stamberger, H., Deconinck, T., Oprescu, S. N., Partoens, M., Zhang, Y., Sourbron, J., Adriaenssens, E., Mullen, P., Wiencek, P., Hardies, K., Lee, J. S., Giong, H. K., Distelmaier, F., Elpeleg, O., Helbig, K. L., Hersh, J., Isikay, S., Jordan, E., ... De Jonghe, P. (2019). Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. Nature Communications, 10, [708]. https://doi.org/10.1038/s41467-018-07953-w Go to publication entry in University of Southern Denmark's Research Portal ARTICLE https://doi.org/10.1038/s41467-018-07953-w OPEN Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish Aleksandra Siekierska, Hannah Stamberger et al.# Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as 1234567890():,; a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies. Correspondence and requests for materials should be addressed to P.d.W. (email: [email protected]) or to P.D.J. (email: [email protected]). #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2019) 10:708 | https://doi.org/10.1038/s41467-018-07953-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-018-07953-w minoacyl tRNA synthetases (ARSs) play a key role in mo, median 4.3 mo). Seizure types included generalized or protein translation as they catalyze the attachment of bilateral tonic-clonic seizures (seven patients), myoclonia (four A fi speci c amino acids to their cognate transfer RNA patients), tonic seizures (one patient), focal seizures (two (tRNA) molecules1,2. The nuclear encoded ARS gene loci are patients), and atypical absences (one patient). In patient 2, subdivided into 17 cytoplasmic, 17 mitochondrial, and three bi- migrating focal seizures were documented on EEG. In four functional ARSs3,4. The canonical aminoacylation and proof- patients more than two anti-epileptic drug regimens failed reading functions of ARSs are highly conserved across species. In meeting the definition of drug resistance25. No seizures were addition, during evolution many ARSs acquired additional observed in patients 4 and 5 (family III), and repeated EEGs were domains with unique structural characteristics that are not normal. Both siblings were reported to have a notably happy essential for tRNA charging but account for non-canonical demeanor resembling Angelman syndrome, but genetic testing functions5,6. These alternative functions are critical for cellular for this syndrome was negative. homeostasis and include among others: regulation of signal Other clinical neurological features included (axial) hypotonia transduction and cell migration, angiogenesis and tumorigenesis, (four patients), spasticity (five patients), and an ataxic gait (two inflammatory responses, and control of cell death5. This func- patients). Three patients were reported to have significant sleep tional diversity may in part account for the association between problems. Brain imaging showed cerebral atrophy in eight mutations in ARS genes and a broad range of human disorders, patients and atrophy or partial agenesis of the corpus callosum including neurological disorders, cancer, and auto-immune in four patients. Furthermore, hypomyelination or delayed diseases2. myelination was reported in four patients. All patients had a Both monoallelic and biallelic pathogenic variants in ARS severe, progressive microcephaly on the background of a more genes, encoding dominant and recessive disease traits, respec- general failure-to-thrive. Patients 9 and 10 (carrying the same tively, have been increasingly reported in patients with various VARS variant) had additional systemic features including post- disorders that often have predominantly neurological features. natal anemia and hepatosplenomegaly in patient 9. Patient 10 Dominant heterozygous mutations in ARS genes have been died at the age of 3 years as a consequence of septic shock with no identified in patients with Charcot-Marie-Tooth disease and history of immunodeficiency. A detailed summary of the clinical related peripheral neuropathies, including AARS7, GARS8, findings in all patients is provided in Supplementary Data 1. HARS9,10, MARS11,12, WARS13, and YARS12,14. Recessive muta- All patients were referred for genetic testing with WES or whole- tions have been identified in complex disorders often involving genome sequencing (WGS) after standard diagnostic work-up did the central nervous system such as hypomyelination with brain- not reveal a cause for their neurodevelopmental disorder (details stem and spinal cord involvement (DARS)15, leukodystrophy available in Supplementary Notes 1 to 6). Three compound (RARS)16, congenital visual impairment and progressive micro- heterozygous VARS variants were identified in the affected cephaly (KARS)17, developmental delay with progressive micro- members of families I (p.Leu434Val/p.Gly822Ser), II (p.Gln400Pro/ cephaly and intractable seizures (QARS)18,19 and early onset p.Arg442Gln), and III (p.Leu78Argfs*35/p.Arg942Gln). Of note, in epileptic encephalopathy with myelination defect (AARS)20. addition to the biallelic VARS variant, patient 3 also carried a rare de Interestingly, some ARS genes have been associated with both novo variant of uncertain significance in the brain expressed gene dominant and recessive disease traits including mutations in UBE2O which has been reported 1 time in the Exome Aggregation AARS7,20, KARS21, and YARS14,22. Constortium (ExAC)26 (OMIM 617649, Supplementary Note 2). In this study, we report five newly diagnosed families with Two homozygous missense variants identified in families IV biallelic variants in valyl-tRNA synthetase (VARS), including (p.Leu885Phe) and V (p.Arg1058Gln) were previously reported in seven novel VARS variants. In addition, we present an in-depth a large study on brain malformations in mainly consanguineous description of two families previously reported in a large study on families23 and in families VI (Jordan ancestry) and VII (Israel/Arabic brain malformations in mainly consanguineous families wherein ancestry), the same, homozygous, p.Arg404Trp variant was identi- VARS was reported as a candidate disease gene23. In vitro studies fied. All VARS variants were deemed pathogenic based on their with patient-derived cell lines, including enzymatic assays, and absence or presence in very low frequency in ExAC and the Genome yeast complementation assays show that recessive VARS muta- Aggregation Database (gnomAD)26, impact on protein level, different tions most likely lead to a loss-of-protein function, i.e. loss of prediction tools, and segregation (Supplementary Table 1). All function (LoF) alleles. A vars knockout (KO) zebrafish model identified variants were located in the catalytic or the anticodon- further demonstrates that deficiency of vars results in micro- binding domain of the protein with the exception of the frameshift cephaly and epileptiform activity, replicating key characteristics variant, which was not located in a specificdomain(Fig.1b). of the human disease. In silico modeling in T. thermophilus ValRS. To gain insights Results into the potential structural and functional consequences of the Biallelic VARS variants cause developmental encephalopathy. human missense variants, the sequence of the human enzyme was In total, ten patients from seven families with biallelic VARS aligned to ValRS sequences from various taxa (Supplementary
Load more

Recommended publications
  • Strains Used in Whole Organism Plasmodium Falciparum Vaccine Trials Differ in 2 Genome Structure, Sequence, and Immunogenic Potential 3 4 Authors: Kara A
    bioRxiv preprint doi: https://doi.org/10.1101/684175; this version posted June 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Title: Strains used in whole organism Plasmodium falciparum vaccine trials differ in 2 genome structure, sequence, and immunogenic potential 3 4 Authors: Kara A. Moser1‡, Elliott F. Drábek1, Ankit Dwivedi1, Jonathan Crabtree1, Emily 5 M. Stucke2, Antoine Dara2, Zalak Shah2, Matthew Adams2, Tao Li3, Priscila T. 6 Rodrigues4, Sergey Koren5, Adam M. Phillippy5, Amed Ouattara2, Kirsten E. Lyke2, Lisa 7 Sadzewicz1, Luke J. Tallon1, Michele D. Spring6, Krisada Jongsakul6, Chanthap Lon6, 8 David L. Saunders6¶, Marcelo U. Ferreira4, Myaing M. Nyunt2§, Miriam K. Laufer2, Mark 9 A. Travassos2, Robert W. Sauerwein7, Shannon Takala-Harrison2, Claire M. Fraser1, B. 10 Kim Lee Sim3, Stephen L. Hoffman3, Christopher V. Plowe2§, Joana C. Silva1,8 11 12 Corresponding author: Joana C. Silva, [email protected] 13 Affiliations: 14 1 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, 15 MD, 21201 16 2 Center for Vaccine Development and Global Health, University of Maryland School of 17 Medicine, Baltimore, MD, 21201 18 3 Sanaria, Inc. Rockville, Maryland, 20850 19 4 Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 20 São Paulo, Brazil 21 5 Genome Informatics Section, Computational and Statistical Genomics Branch, 22 National Human
    [Show full text]
  • Aminoacyl-Trna Synthetase Deficiencies in Search of Common Themes
    © American College of Medical Genetics and Genomics ARTICLE Aminoacyl-tRNA synthetase deficiencies in search of common themes Sabine A. Fuchs, MD, PhD1, Imre F. Schene, MD1, Gautam Kok, BSc1, Jurriaan M. Jansen, MSc1, Peter G. J. Nikkels, MD, PhD2, Koen L. I. van Gassen, PhD3, Suzanne W. J. Terheggen-Lagro, MD, PhD4, Saskia N. van der Crabben, MD, PhD5, Sanne E. Hoeks, MD6, Laetitia E. M. Niers, MD, PhD7, Nicole I. Wolf, MD, PhD8, Maaike C. de Vries, MD9, David A. Koolen, MD, PhD10, Roderick H. J. Houwen, MD, PhD11, Margot F. Mulder, MD, PhD12 and Peter M. van Hasselt, MD, PhD1 Purpose: Pathogenic variations in genes encoding aminoacyl- with unreported compound heterozygous pathogenic variations in tRNA synthetases (ARSs) are increasingly associated with human IARS, LARS, KARS, and QARS extended the common phenotype disease. Clinical features of autosomal recessive ARS deficiencies with lung disease, hypoalbuminemia, anemia, and renal tubulo- appear very diverse and without apparent logic. We searched for pathy. common clinical patterns to improve disease recognition, insight Conclusion: We propose a common clinical phenotype for recessive into pathophysiology, and clinical care. ARS deficiencies, resulting from insufficient aminoacylation activity Methods: Symptoms were analyzed in all patients with recessive to meet translational demand in specific organs or periods of life. ARS deficiencies reported in literature, supplemented with Assuming residual ARS activity, adequate protein/amino acid supply unreported patients evaluated in our hospital. seems essential instead of the traditional replacement of protein by Results: In literature, we identified 107 patients with AARS, glucose in patients with metabolic diseases. DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies.
    [Show full text]
  • Anti-VARS (Aa 994-1102) Polyclonal Antibody (DPAB-DC3179) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-VARS (aa 994-1102) polyclonal antibody (DPAB-DC3179) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Antigen Description Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. Immunogen VARS (NP_006286, 994 a.a. ~ 1102 a.a) partial recombinant protein with GST tag. The sequence is AVRLSNQGFQAYDFPAVTTAQYSFWLYELCDVYLECLKPVLNGVDQVAAECARQTLYTCLDVG LRLLSPFMPFVTEELFQRLPRRMPQAPPSLCVTPYPEPSECSWKDP Source/Host Mouse Species Reactivity Human Conjugate Unconjugated Applications WB (Recombinant protein), ELISA, Size 50 μl Buffer 50 % glycerol Preservative None Storage Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing. GENE INFORMATION Gene Name VARS valyl-tRNA synthetase [ Homo sapiens (human) ] Official Symbol VARS Synonyms VARS; valyl-tRNA synthetase; G7A; VARS1; VARS2; valine--tRNA ligase; valRS; protein G7a; valyl-tRNA synthetase 2; valine tRNA ligase 1, cytoplasmic; 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Entrez Gene ID 7407 Protein Refseq NP_006286 UniProt ID A0A024RCN6 Chromosome Location 6p21.3 Pathway Aminoacyl-tRNA biosynthesis; Cytosolic tRNA aminoacylation; tRNA Aminoacylation; Function ATP binding; aminoacyl-tRNA editing activity; valine-tRNA ligase activity; 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 2 © Creative Diagnostics All Rights Reserved.
    [Show full text]
  • Pfswib, a Potential Chromatin Regulator for Var Gene Regulation and Parasite Development in Plasmodium Falciparum Wei‑Feng Wang1,3† and Yi‑Long Zhang2,3*†
    Wang and Zhang Parasites Vectors (2020) 13:48 https://doi.org/10.1186/s13071-020-3918-5 Parasites & Vectors RESEARCH Open Access PfSWIB, a potential chromatin regulator for var gene regulation and parasite development in Plasmodium falciparum Wei‑Feng Wang1,3† and Yi‑Long Zhang2,3*† Abstract Background: Various transcription factors are involved in the process of mutually exclusive expression and clonal variation of the Plasmodium multigene (var) family. Recent studies revealed that a P. falciparum SWI/SNF‑related matrix‑associated actin‑dependent regulator of chromatin (PfSWIB) might trigger stage‑specifc programmed cell death (PCD), and was not only crucial for the survival and development of parasite, but also had profound efects on the parasite by interacting with other unknown proteins. However, it remains unclear whether PfSIWB is involved in transcriptional regulation of this virulence gene and its functional properties. Methods: A conditional knockdown system “PfSWIB‑FKBP‑LID” was introduced to the parasite clone 3D7, and an integrated parasite line “PfSWIB‑HA‑FKBP‑LID” was obtained by drug cycling and clone screening. Growth curve analysis (GCA) was performed to investigate the growth and development of diferent parasite lines during 96 h in vitro culturing, by assessing parasitemia. Finally, we performed qPCR assays to detect var gene expression profling in various comparison groups, as well as the mutually exclusive expression pattern of the var genes within a single 48 h life‑cycle of P. falciparum in diferent parasite lines. In addition, RNA‑seq was applied to analyze the var gene expres‑ sion in diferent lines. Results: GCA revealed that conditional knockdown of PfSWIB could interfere with the growth and development of P.
    [Show full text]
  • Downregulation of SNRPG Induces Cell Cycle Arrest and Sensitizes Human Glioblastoma Cells to Temozolomide by Targeting Myc Through a P53-Dependent Signaling Pathway
    Cancer Biol Med 2020. doi: 10.20892/j.issn.2095-3941.2019.0164 ORIGINAL ARTICLE Downregulation of SNRPG induces cell cycle arrest and sensitizes human glioblastoma cells to temozolomide by targeting Myc through a p53-dependent signaling pathway Yulong Lan1,2*, Jiacheng Lou2*, Jiliang Hu1, Zhikuan Yu1, Wen Lyu1, Bo Zhang1,2 1Department of Neurosurgery, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China;2 Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China ABSTRACT Objective: Temozolomide (TMZ) is commonly used for glioblastoma multiforme (GBM) chemotherapy. However, drug resistance limits its therapeutic effect in GBM treatment. RNA-binding proteins (RBPs) have vital roles in posttranscriptional events. While disturbance of RBP-RNA network activity is potentially associated with cancer development, the precise mechanisms are not fully known. The SNRPG gene, encoding small nuclear ribonucleoprotein polypeptide G, was recently found to be related to cancer incidence, but its exact function has yet to be elucidated. Methods: SNRPG knockdown was achieved via short hairpin RNAs. Gene expression profiling and Western blot analyses were used to identify potential glioma cell growth signaling pathways affected by SNRPG. Xenograft tumors were examined to determine the carcinogenic effects of SNRPG on glioma tissues. Results: The SNRPG-mediated inhibitory effect on glioma cells might be due to the targeted prevention of Myc and p53. In addition, the effects of SNRPG loss on p53 levels and cell cycle progression were found to be Myc-dependent. Furthermore, SNRPG was increased in TMZ-resistant GBM cells, and downregulation of SNRPG potentially sensitized resistant cells to TMZ, suggesting that SNRPG deficiency decreases the chemoresistance of GBM cells to TMZ via the p53 signaling pathway.
    [Show full text]
  • Downloaded Per Proteome Cohort Via the Web- Site Links of Table 1, Also Providing Information on the Deposited Spectral Datasets
    www.nature.com/scientificreports OPEN Assessment of a complete and classifed platelet proteome from genome‑wide transcripts of human platelets and megakaryocytes covering platelet functions Jingnan Huang1,2*, Frauke Swieringa1,2,9, Fiorella A. Solari2,9, Isabella Provenzale1, Luigi Grassi3, Ilaria De Simone1, Constance C. F. M. J. Baaten1,4, Rachel Cavill5, Albert Sickmann2,6,7,9, Mattia Frontini3,8,9 & Johan W. M. Heemskerk1,9* Novel platelet and megakaryocyte transcriptome analysis allows prediction of the full or theoretical proteome of a representative human platelet. Here, we integrated the established platelet proteomes from six cohorts of healthy subjects, encompassing 5.2 k proteins, with two novel genome‑wide transcriptomes (57.8 k mRNAs). For 14.8 k protein‑coding transcripts, we assigned the proteins to 21 UniProt‑based classes, based on their preferential intracellular localization and presumed function. This classifed transcriptome‑proteome profle of platelets revealed: (i) Absence of 37.2 k genome‑ wide transcripts. (ii) High quantitative similarity of platelet and megakaryocyte transcriptomes (R = 0.75) for 14.8 k protein‑coding genes, but not for 3.8 k RNA genes or 1.9 k pseudogenes (R = 0.43–0.54), suggesting redistribution of mRNAs upon platelet shedding from megakaryocytes. (iii) Copy numbers of 3.5 k proteins that were restricted in size by the corresponding transcript levels (iv) Near complete coverage of identifed proteins in the relevant transcriptome (log2fpkm > 0.20) except for plasma‑derived secretory proteins, pointing to adhesion and uptake of such proteins. (v) Underrepresentation in the identifed proteome of nuclear‑related, membrane and signaling proteins, as well proteins with low‑level transcripts.
    [Show full text]
  • New Insights on Human Essential Genes Based on Integrated Multi
    bioRxiv preprint doi: https://doi.org/10.1101/260224; this version posted February 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. New insights on human essential genes based on integrated multi- omics analysis Hebing Chen1,2, Zhuo Zhang1,2, Shuai Jiang 1,2, Ruijiang Li1, Wanying Li1, Hao Li1,* and Xiaochen Bo1,* 1Beijing Institute of Radiation Medicine, Beijing 100850, China. 2 Co-first author *Correspondence: [email protected]; [email protected] Abstract Essential genes are those whose functions govern critical processes that sustain life in the organism. Comprehensive understanding of human essential genes could enable breakthroughs in biology and medicine. Recently, there has been a rapid proliferation of technologies for identifying and investigating the functions of human essential genes. Here, according to gene essentiality, we present a global analysis for comprehensively and systematically elucidating the genetic and regulatory characteristics of human essential genes. We explain why these genes are essential from the genomic, epigenomic, and proteomic perspectives, and we discuss their evolutionary and embryonic developmental properties. Importantly, we find that essential human genes can be used as markers to guide cancer treatment. We have developed an interactive web server, the Human Essential Genes Interactive Analysis Platform (HEGIAP) (http://sysomics.com/HEGIAP/), which integrates abundant analytical tools to give a global, multidimensional interpretation of gene essentiality. bioRxiv preprint doi: https://doi.org/10.1101/260224; this version posted February 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • Secondary Functions and Novel Inhibitors of Aminoacyl-Trna Synthetases Patrick Wiencek University of Vermont
    University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2018 Secondary Functions And Novel Inhibitors Of Aminoacyl-Trna Synthetases Patrick Wiencek University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Biochemistry Commons Recommended Citation Wiencek, Patrick, "Secondary Functions And Novel Inhibitors Of Aminoacyl-Trna Synthetases" (2018). Graduate College Dissertations and Theses. 941. https://scholarworks.uvm.edu/graddis/941 This Thesis is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. SECONDARY FUNCTIONS AND NOVEL INHIBITORS OF AMINOACYL-TRNA SYNTHETASES A Thesis Presented by Patrick Wiencek to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Master of Science Specializing in Biochemistry October, 2018 Defense Date: June 29, 2018 Thesis Examination Committee: Christopher S. Francklyn, Ph.D., Advisor Karen M. Lounsbury, Ph.D., Chairperson Robert J. Hondal, Ph.D. Jay Silveira, Ph.D. Cynthia J. Forehand, Ph.D., Dean of the Graduate College ABSTRACT The aminoacyl-tRNA synthetases are a family of enzymes involved in the process of translation, more specifically, ligating amino acids to their cognate tRNA molecules. Recent evidence suggests that aminoacyl-tRNA synthetases are capable of aminoacylating proteins, some of which are involved in the autophagy pathway. Here, we test the conditions under which E. coli and human threonyl-tRNA synthetases, as well as hisidyl-tRNA synthetase aminoacylate themselves.
    [Show full text]
  • Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen
    CLINICAL RESEARCH www.jasn.org Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen Rany M. Salem ,1 Jennifer N. Todd,2,3,4 Niina Sandholm ,5,6,7 Joanne B. Cole ,2,3,4 Wei-Min Chen,8 Darrell Andrews,9 Marcus G. Pezzolesi,10 Paul M. McKeigue,11 Linda T. Hiraki,12 Chengxiang Qiu,13 Viji Nair,14 Chen Di Liao,12 Jing Jing Cao,12 Erkka Valo ,5,6,7 Suna Onengut-Gumuscu,8 Adam M. Smiles,15 Stuart J. McGurnaghan,16 Jani K. Haukka,5,6,7 Valma Harjutsalo,5,6,7,17 Eoin P. Brennan,9 Natalie van Zuydam,18,19 Emma Ahlqvist,20 Ross Doyle,9 Tarunveer S. Ahluwalia ,21 Maria Lajer,21 Maria F. Hughes,9 Jihwan Park,13 Jan Skupien,15 Athina Spiliopoulou,11 Andrew Liu,22 Rajasree Menon,14,23 Carine M. Boustany-Kari,24 Hyun M. Kang,23,25 Robert G. Nelson,26 Ronald Klein,27 Barbara E. Klein,27 Kristine E. Lee ,27 Xiaoyu Gao,28 Michael Mauer,29 Silvia Maestroni,30 Maria Luiza Caramori,29 Ian H. de Boer ,31 Rachel G. Miller,32 Jingchuan Guo ,32 Andrew P. Boright,12 David Tregouet,33,34 Beata Gyorgy,33,34 Janet K. Snell-Bergeon,35 David M. Maahs,36 Shelley B. Bull ,37 Angelo J. Canty,38 Colin N.A. Palmer,39 Lars Stechemesser,40 Bernhard Paulweber,40 Raimund Weitgasser,40,41 Jelizaveta Sokolovska,42 Vita Rovıte,43 Valdis Pırags, 42,44 Edita Prakapiene,45 Lina Radzeviciene,46 Rasa Verkauskiene,46 Nicolae Mircea Panduru,6,47 Leif C.
    [Show full text]
  • Supporting Information
    Supporting Information Poulogiannis et al. 10.1073/pnas.1009941107 SI Materials and Methods Loss of Heterozygosity (LOH) Analysis of PARK2. Seven microsatellite Bioinformatic Analysis of Genome and Transcriptome Data. The markers (D6S1550, D6S253, D6S305, D6S955, D6S980, D6S1599, aCGH package in R was used to identify significant DNA copy and D6S396) were amplified for LOH analysis within the PARK2 number (DCN) changes in our collection of 100 sporadic CRCs locus using primers that were previously described (8). (1) (Gene Expression Omnibus, accession no. GSE12520). The MSP of the PARK2 Promoter. CpG sites within the PARK2 promoter aCGH analysis of cell lines and liver metastases was derived region were detected using the Methprimer software (http://www. from published data (2, 3). Chromosome 6 tiling-path array- urogene.org/methprimer/index.html). Methylation-specificand CGH was used to identify the smallest and most frequently al- control primers were designed using the Primo MSP software tered regions of DNA copy number change on chromosome 6. (http://www.changbioscience.com/primo/primom.html); bisulfite An integrative approach was used to correlate expression pro- modification of genomic DNA was performed as described pre- files with genomic copy number data from a SNP array from the viously (9). All tumor DNA samples from primary CRC tumors same tumors (n = 48) (4) (GSE16125), using Pearson’s corre- (n = 100) and CRC lines (n = 5), as well as those from the leukemia lation coefficient analysis to identify the relationships between cell lines KG-1a (acute myeloid leukemia, AML), U937 (acute DNA copy number changes and gene expression of those genes lymphoblastic leukemia, ALL), and Raji (Burkitt lymphoma, BL) SssI located within the small frequently altered regions of DCN were screened as part of this analysis.
    [Show full text]
  • Package 'Canprot'
    Package ‘canprot’ October 19, 2020 Date 2020-10-19 Version 1.1.0 Title Compositional Analysis of Differentially Expressed Proteins in Cancer Maintainer Jeffrey Dick <[email protected]> Depends R (>= 3.1.0) Imports xtable, MASS, rmarkdown Suggests CHNOSZ (>= 1.3.0), knitr, testthat Description Compositional analysis of differentially expressed proteins in cancer and cell culture proteomics experiments. The data include lists of up- and down-regulated proteins in different cancer types (breast, colorectal, liver, lung, pancreatic, prostate) and laboratory conditions (hypoxia, hyperosmotic stress, high glucose, 3D cell culture, and proteins secreted in hypoxia), together with amino acid compositions computed for protein sequences obtained from UniProt. Functions are provided to calculate compositional metrics including protein length, carbon oxidation state, and stoichiometric hydration state. In addition, phylostrata (evolutionary ages) of protein-coding genes are compiled using data from Liebeskind et al. (2016) <doi:10.1093/gbe/evw113> or Trigos et al. (2017) <doi:10.1073/pnas.1617743114>. The vignettes contain plots of compositional differences, phylostrata for human proteins, and references for all datasets. Encoding UTF-8 License GPL (>= 2) BuildResaveData no VignetteBuilder knitr URL https://github.com/jedick/canprot NeedsCompilation no Author Jeffrey Dick [aut, cre] (<https://orcid.org/0000-0002-0687-5890>), Ben Bolker [ctb] (<https://orcid.org/0000-0002-2127-0443>) Repository CRAN Date/Publication 2020-10-19 04:30:02 UTC 1 2 canprot-package R topics documented: canprot-package . .2 check_IDs . .3 cleanup . .4 CLES ............................................6 diffplot . .8 get_comptab . 10 human . 12 metrics . 13 mkvig . 16 pdat_ . 17 protcomp . 19 PS.............................................. 20 qdist . 21 xsummary . 22 Index 24 canprot-package Compositional Analysis of Differentially Expressed Proteins Description canprot is a package for analysis of the chemical compositions of proteins from their amino acid compositions.
    [Show full text]
  • Rabbit Anti-Valyl Trna/FITC Conjugated Antibody-SL10504R
    SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-valyl tRNA/FITC Conjugated antibody SL10504R-FITC Product Name: Anti-valyl tRNA/FITC Chinese Name: FITC标记的缬氨酰-tRNA合成酶抗体 SYVM_HUMAN; Valine--tRNA ligase, mitochondrial; Valyl-tRNA synthetase; Alias: ValRS; Valyl-tRNA synthetase-like; valyl tRNA; VARS2; KIAA1885; VARS2L; VARSL. Organism Species: Rabbit Clonality: Polyclonal React Species: Human,Mouse,Rat,Pig,Cow,Horse,Sheep, ICC=1:50-200IF=1:50-200 Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 115kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human vars2 Lsotype: IgG Purification: affinity purified by Protein A Storage Buffer: 0.01Mwww.sunlongbiotech.com TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibody is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: ValRS (valyl-tRNA synthetase), also known as Protein G7a, belongs to the class-I aminoacyl-tRNA synthetase family that includes the related proteins, LeuRS and IleRS. These proteins are large monomeric proteins and play a major role in catalyzing the Product Detail: aminoacylation of tRNA by their cognate amino acid. ValRS joins Val to tRNA(Val) at its synthetic active site.
    [Show full text]