DOCSLIB.ORG

A Final Solution to the Ethylmalonic Acid Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Final Solution to the Ethylmalonic Acid Syndrome An almost final solution to the Ethylmalonic acid syndrome Valeria Tiranti ERNDIM Meeting October 22-23, 2009 Basel Ethylmalonic Encephalopathy (EE) urea 9 e 8 c n ethylmalonate a 7 d 2-ketoglutarate n u 6 b A 5 4 isobutyrylglycine 3 I.S. isovalerylglycine I.S. 2 1 Time 0 COOH CH3-CH2-CH2-CO-SCoA + CO2 -> CH3-CH2-CH-COOH Butyryl-CoA Ethylmalonate CNS CoASH •early-onset hypotonia. developmental delay •later spasticity, then global failure Vascular system •acrocyanosis •petechiae, microematuria, internal bleedings Gastrointestinal system •chronic diarrhoea Biochemistry •COX deficiency (only in muscle) •lactic acidosis •ethylmalonic aciduria •elevated C4-C5 acylcarnitine 440del11 ETHE1: the gene 505+1G>A 406A>G 487C>T 3G>T 187C>T 505+1G>T 604insG GCCCCdel 376-1G>T 488G>A 113A>G 131delAG 559insC 50 EE 375+5G>A 222insA 482G>A 554T>G 34C>T 230delA patients 1 2 3 4 5 6 7 7 28 non-EE EX4del EMA patients EX1-7del Ethe1: the protein HeLa It is a mitochondrial matrix protein ETHE1 merge Mitotracker It works as an homodimer Fe++ It binds iron Tiranti et al 2004-2006, Mineri et al 2008 ETHE1-/- mouse phenotype +/+ %) 14 ( +/+ 12 10 8 -/- grams 6 4 2 Survival probability -/- 0 1 2 3 4 weeks days Metabolites in body fluids 400 C4 acylcarnitine C5 acylcarnitine 350 Ethylmalonic acid 300 4,5 250 18 4 16 3,5 200 14 3 /L 12 /L 150 M 2,5 M µ 10 µ 2 8 /mg creatinine 100 1,5 g 6 µ 4 1 50 2 0,5 0 0 0 CTR KO CTR EE-patients CTR KO CTR EE-patients CTR KO CTR EE-patients mouse human mouse human mouse human Respiratory chain complex activities in mouse tissues 200 Liver Kidney 150 liver 100 50 0 +/+ -/- +/+ -/- +/+ -/- +/+ -/- brain CI/CS CIV/CS CI/CS CIV/CS 200 Muscle Brain 150 100 muscle 50 ** ** 0 +/+ -/- +/+ -/- +/+ -/- +/+ -/- CI/CS CIV/CS CI/CS CIV/CS 200 Heart colon 150 100 ** 50 0 ** p<0.0004 +/+ -/- +/+ -/- jejunum CI/CS CIV/CS -/- +/+ Western-blot analysis of COX assembly in ETHE1 KO mice BRAIN LIVER MUSCLE +/+ -/- +/+ -/- +/+ -/- S1 COI I dimension Heme A COI Cox10p Cox11p Heme A3 Cox14p ? Cu B Sco1p Cox17p Cox15p Sco2p COIV Pet100p Pet117p ? S2 COII Cu A Sco1p Cox17p SDH Pet191p Sco2p Surf1 COIII Oxa1p ? COVa, Vb, VIc, VIIa, VIII COVIb Lon Afg3 ? COVIIc Rca1 BRAIN S3 COVIIb COVIa +/+ S4 II dimension on Brain -/- COI Bioinformatic search ETHE1-like proteins are present in operons containing Rhodanese-like proteins or as Chimeric proteins ETHE1/Rhodanese Fusion events Operon Polaromonas sp. 54032671 9 F Bradyrhizobium japonicum 27376118 9 soxX soxY soxZ soxA ?? soxB ?? Legionella pneumophila 54293763 9 Legionella pneumophila 52841017 9 Danio rerio 47086181 9 Caenorhabditis elegans 17538952 9 Apis mellifera 48140497 9 Drosophila melanogaster 24652740 9 Drosophila melanogaster 27819799 9 Zn-hydrolase domain Anopheles gambiae 31210533 9 Anopheles gambiae 55240363 9 Rhodanese-related sulfurtransferase domain ‏ Oryza sativa 56202167 9 ?? Domain of unknown function Oryza sativa 34910930 9 ‏ Arabidopsis thaliana 12324040 9 Predicted permease Arabidopsis thaliana 1644427 9 Gluthation S-transferase ‏ Arabidopsis thaliana 22655048 9 Sulfur oxidase gene cluster Xenopus laevis 27371293 9 Pan troglodytes 55649315 9 Homo sapiens ETHE1 Mus musculus 53236965 9 Rattus norvegicus 27676450 9 Burkholderia cepacia 46322841 9 F Burkholderia cepacia 46317848 9 F Ralstonia eutropha 45515657 9 Ralstonia metallidurans 48771425 9 Nostoc punctiforme 23128919 9 F ?? ?? Synechococcus elongatus 56750614 9 Nostoc sp. 17231396 9 Anabaena variabilis 45507470 9 Synechocystis sp. 16330445 9 ?? Thermosynechococcus elongatus 22299169 9 RHODANESE (TST, Thiosulphate Sulfurtrasferase)‏ Mitochondrial matrix protein Unknown biological function (Cyanide detoxyfication, Iron-sulfur cluster formation, energetic metabolism) It is involved in sulfur metabolism Sulfur metabolism Thiosulphate in urines 20000 18000 16000 2500 14000 12000 2000 10000 1500 8000 6000 /mg creatinine 1000 /mg creatinine 4000 500 nmol nmol 2000 0 0 CTR EE-Patients CTR KO mice 200 and tissues 160 120 M µ 80 40 0 Szabo, Nat Rev Drug Discov 2007 +/+ -/- +/+ -/- +/+ -/- +/+ -/- +/+ -/- brain liver muscle kidney serum H2S concentration in tissues of ETHE1 knockout mice MUSCLE LIVER 2500,0 3500,0 3000,0 2000,0 p<0.0007 2500,0 p=0.00007 1500,0 2000,0 1500,0 1000,0 1000,0 500,0 500,0 0,0 0,0 CTR KO CTR KO BRAIN 90,0 80,0 70,0 ) p<0.0016 M 60,0 n ( 50,0 S 40,0 2 H 30,0 20,0 10,0 0,0 CTR KO H2S inhibits cytochrome c oxidase (COX) Szabo, Nat Rev Drug Discov 2007 H2S inhibits enzymatic activities 120 120 100 100 80 MUSCLE 80 COX/CS SCAD in liver BRAIN 60 60 LIVER 40 4residual activity 0 NaCN residual activity 20 20 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 200 400 600 800 1000 1200 NaSH (µM) NaSH (µM) 120 100 CI/CS 80 CS CI and CS in muscle 60 40 residual activity 20 0 0 2 4 6 8 10 12 NaSH (µM) Conclusions 1 •The pathogenetic mechanism of Ethylmalonic Encephalopathy (EE) relies on high levels of H2S, that are toxic for both COX and SCAD •H2S can act as a vasodilator thus explaining the acrocyanosis and can be toxic for the microvessels thus explaining the petechiae Which is the role of ETHE1???? H2S (sulfide) is the first inorganic substrate for mitochondrial respiratory chain in mammals SQR SDO H2S RSSH+H2O+O2 H2SO3 sulfide quinone sulfur dioxygenase oxidoreductase TST sulfur tranferase H2S2O3 H2S2O3 (thiosulfate) H2O H2SO3 (sulfite) O2 SDO TST/Rhodanese (SDO: Sulfur Dioxygenase) (Thiosulfate Sulfur Transferase) 2H2S R -SSH R -SSH (hydrogen sulfide) (persulfide) (persulfide) e- S S O2 2H2O R (SQR: Sulfide quinone matrix Oxidoreductase) SQR UQ inner mitochondrial - - membrane e e UQH2 Cyt c intermembrane space CIII e- CIV SDO activity in liver of ETHE1 -/- homogenates 10 Sulfide ) 9 8 7 mol/mg/min 6 n 5 4 Liver 3 -/- +/+ ETHE1 SDO activity ( 2 1 SDH 0 +/+ -/- liver homogenate H2S2O3 H2SO3 (sulfite) ETHE1 Rhodanese (SDO: Sulfur Dioxygenase) (Thiosulfate Sulfur Transferase) R -SSH R -SSH H2S (persulfide) (persulfide) e- S S O2 2H2O R (SQR: Sulfide quinone matrix Oxidoreductase) SQR UQ inner mitochondrial - - membrane e e UQH2 Cyt c intermembrane space CIII e- CIV Conclusions 2 .ETHE1, encodes a mitochondrial sulfur dioxygenase that takes part in aerobic energetic exploitation of, and detoxification from, H2S .EE is the first example of a mitochondrial disorder caused by genetically determined poisoning of the respiratory chain .The creation of organ-specific conditional KO animals, can be useful to identify the main source of H2S generation in EE, e.g. exogenous absorption from the gut flora vs. endogenous production H2S-producing gut flora and mucosal COX 101-103 cfu/ml 1011-1012 cfu/ml 104-107 cfu/ml H&E COX WT KO KO WT .The toxic mechanism underpinning Ethylmalonic Encephalopathy makes effective therapy a realistic goal: for instance antibiotic control of H2S-producing bacterial flora vs. H2S neutralization using GSH as a sulfide acceptor Final considerations and future perspectives A specific treatment against the proliferation of H2S-producing anaerobic bacterial flora in the large intestine leads to substantial improvement of the clinical conditions in experimental murine EE (1) the diffusion of H2S through the colonic mucosa could be a major, but not the only cause of disease in Ethe1-/- mice and patients (2) the restriction of bacterial production of H2S and its neutralization by NAC, may be therapeutically beneficial in the mouse, and possibly human, disease condition. THANK YOU!! Unit of Molecular Neurogenetics Massimo Zeviani Barbara Garavaglia Eleonora Lamantea Carlo Viscomi Ivano DiMeo Rossana Mineri Egill Briem Collaborations Tatjana Hildebrandt Mike Levitt Marco Rimoldi Alessandro Prelle Gigliola Fagiolari Cecilia Tiveron All the clinicians world-wide who referred the patients to our Centre.
Load more

Recommended publications
  • Child Neurology: Ethylmalonic Encephalopathy
    Published Ahead of Print on February 28, 2020 as 10.1212/WNL.0000000000009144 RESIDENT & FELLOW SECTION Child Neurology: Ethylmalonic encephalopathy Periyasamy Govindaraj, PhD, Bindu Parayil Sankaran, FRACP, Madhu Nagappa, DM, Correspondence Hanumanthapura R. Arvinda, DM, Sekar Deepha, MSc, J.N. Jessiena Ponmalar, MSc, Sanjib Sinha, DM, Dr. Parayil Sankaran Narayanappa Gayathri, PhD, and Arun B. Taly, DM Bindu.parayilsankaran@ health.nsw.gov.au Neurology® 2020;94:e1-e4. doi:10.1212/WNL.0000000000009144 Ethylmalonic encephalopathy (EE; OMIM #602473) is an autosomal recessive disorder char- MORE ONLINE acterized by (1) progressive neurologic impairment, including global developmental delay with Video periods of regression during illness, progressive pyramidal and extrapyramidal signs, and seizures; and (2) generalized microvascular damage, including petechial purpura and chronic hemorrhagic diarrhea. It leads to premature death. EE is caused by mutations in ethylmalonic encephalopathy protein 1 (ETHE1), and more than 60 different mutations have been reported.1,2 ETHE1 encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide 2 fi (H2S). Impairment of sulfur dioxygenase leads to the accumulation of hydrogen sul de and its fl derivatives (thiosulphate) in various body uids and tissues. Higher concentration of H2Sistoxic and induces direct damage to cell membranes. It inhibits cytochrome c oxidase (COX), increases lactic acid and short-chain acyl-COA dehydrogenase, and leads to elevation of ethyl malonate and C4/C5 acylcarnitine in muscle and brain.2 We describe the clinical phenotype and MRI, path- ologic, and biochemical findings of a patient with EE from India who had a novel homozygous c.493 G>C (p.D165H) variation in ETHE1.
    [Show full text]
  • 10.1136/Jmg.2005.036210 J Med Genet: First Published As 10.1136/Jmg.2005.036210 on 23 September 2005
    JMG Online First, published on September 23, 2005 as 10.1136/jmg.2005.036210 J Med Genet: first published as 10.1136/jmg.2005.036210 on 23 September 2005. Downloaded from ETHE1 mutations are specific to Ethylmalonic Encephalopathy V. Tiranti1*, E. Briem 1*, E. Lamantea1, R. Mineri1, E. Papaleo2, L. De Gioia2, F. Forlani3, P. Rinaldo4, P. Dickson5, B. Abu-Libdeh6, L. Cindro-Heberle7, M. Owaidha8, R.M. Jack9, E. Christensen10, A. Burlina11, M. Zeviani1 1Unit of Molecular Neurogenetics – Pierfranco and Luisa Mariani Center for the Study of Children’s Mitochondrial Disorders, National Neurological Institute “C. Besta”, Milan, Italy; 2Department of Biotechnology and Biosciences. University of Milan-Bicocca, Italy; 3Dipartimento di Scienze Molecolari Agro-Alimentari, Facoltà di Agraria, State University of Milan, Italy; 4Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Biochemical Genetics Laboratory, Rochester, MN, USA; 5Harbor-UCLA Medical Center, Division of Medical Genetics, Torrance, CA, USA; 6Makassed Hospital, Mount of Olives, Jerusalem, Israel; 7Paediatric Neurology Unit, Al Sabah Hospital, Kuwait; 8Al-Jahra Hospital, Kuwait; 9Biochemical Genetics lab, Children’s Hospital, Sand Point Way NE, Seattle, WA USA: 10Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark; 11Division of Inborn Metabolic Diseases, Department of Pediatrics, University of Padua, Italy Correspondence to: Massimo Zeviani, MD, PhD Unit of Molecular Neurogenetics National Neurological Institute “Carlo Besta” Via Temolo 4, 20133 Milan, Italy FAX +39-02-23942619 Phone +39-02-23942630 E-mail: [email protected] [email protected] http://jmg.bmj.com/ URL: www.mitopedia.org *The first two authors should be regarded as joint First Authors. on September 24, 2021 by guest.
    [Show full text]
  • Anti-ETHE1 Antibody (ARG57432)
    Product datasheet [email protected] ARG57432 Package: 100 μl anti-ETHE1 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes ETHE1 Tested Reactivity Hu, Ms, Rat Tested Application WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name ETHE1 Antigen Species Human Immunogen Recombinant protein of Human ETHE1. Conjugation Un-conjugated Alternate Names Sulfur dioxygenase ETHE1; EC 1.13.11.18; HSCO; Ethylmalonic encephalopathy protein 1; Persulfide dioxygenase ETHE1, mitochondrial; YF13H12; Hepatoma subtracted clone one protein Application Instructions Application table Application Dilution WB 1:200 - 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control Mouse liver Calculated Mw 28 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer PBS (pH 7.3), 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/2 Bioinformation Gene Symbol ETHE1 Gene Full Name ethylmalonic encephalopathy 1 Background This gene encodes a sulfur dioxygenase that localizes within the mitochondrial matrix. The enzyme functions in sulfide catabolism. Mutations in this gene result in ethylmalonic encephalopathy.[provided by RefSeq, May 2009] Function Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix.
    [Show full text]
  • H2S) Metabolism in Ethylmalonic Encephalopathy
    Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy Valeria Tiranti and Massimo Zeviani Pierfranco and Luisa Mariani Center for Research on Children’s Mitochondrial Disorders, Unit of Molecular Neurogenetics, Institute of Neurology “Carlo Besta,” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan, Italy Correspondence: [email protected]; [email protected] Hydrogen sulfide (sulfide, H2S) is a colorless, water-soluble gas with a typical smell of rotten eggs. In the past, it has been investigated for its role as a potent toxic gas emanating from sewers and swamps or as a by-product of industrial processes. At high concentrations, H2S is a powerful inhibitor of cytochrome c oxidase; in trace amounts, it is an important signaling molecule, like nitric oxide (NO) and carbon monoxide (CO), together termed “gasotransmitters.” This review will cover the physiological role and the pathogenic effects of H2S, focusing on ethylmalonic encephalopathy, a human mitochondrial disorder caused by genetic abnormalities of sulfide metabolism. We will also discuss the options that are now conceivable for preventing genetically driven chronic H2S toxicity, taking into account that a complete understanding of the physiopathology of H2S has still to be achieved. ecause of its fame as a deadly gas, the phys- 4.2.1.22) and cystathionine g-lyase (CSE, EC Biological role of H2S had been long over- 4.4.1.1), which both utilize L-cysteine as a sub- looked, until Abe and Kimura in 1996 (Abe strate (Stipanuk and Beck 1982; Hosoki et al.
    [Show full text]
  • Ethylmalonic Encephalopathy
    Ethylmalonic encephalopathy Description Ethylmalonic encephalopathy is an inherited disorder that affects several body systems, particularly the nervous system. Neurological signs and symptoms include delayed development and the loss of previously acquired skills (developmental regression), weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels (the vascular system) is also affected. Children with this disorder often develop rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy. The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood. Frequency About 70 individuals with this condition have been identified worldwide, mostly in Mediterranean and Arab populations. Although ethylmalonic encephalopathy appears to be very rare, researchers suggest that some cases have been misdiagnosed as other neurological disorders. Causes Ethylmalonic encephalopathy results from mutations in the ETHE1 gene. This gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down sulfide (H2S), a molecule that is critical at very low levels for normal cell functioning but is toxic at high levels. Excess sulfide interferes with numerous cell activities, including mitochondrial energy production. Mutations in the ETHE1 gene lead to the production of a nonfunctional version of the enzyme or prevent any enzyme from being made.
    [Show full text]
  • Structural Enzymology of Sulfide Oxidation by Persulfide Dioxygenase and Rhodanese
    Structural Enzymology of Sulfide Oxidation by Persulfide Dioxygenase and Rhodanese by Nicole A. Motl A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biological Chemistry) in the University of Michigan 2017 Doctoral Committee Professor Ruma Banerjee, Chair Assistant Professor Uhn-Soo Cho Professor Nicolai Lehnert Professor Stephen W. Ragsdale Professor Janet L. Smith Nicole A. Motl [email protected] ORCID iD: 0000-0001-6009-2988 © Nicole A. Motl 2017 ACKNOWLEDGEMENTS I would like to take this opportunity to acknowledge the many people who have provided me with guidance and support during my doctoral studies. First I would like to express my appreciation and gratitude to my advisor Dr. Ruma Banerjee for the mentorship, guidance, support and encouragement she has provided. I would like to thank my committee members Dr. Uhn-Soo Cho, Dr. Nicolai Lehnert, Dr. Stephen Ragsdale and Dr. Janet Smith for their advice, assistance and support. I would like to thank Dr. Janet Smith and members of Dr. Smith’s lab, especially Meredith Skiba, for sharing their expertise in crystallography. I would like to thank Dr. Omer Kabil for his help, suggestions and discussions in various aspects of my study. I would also like to thank members of Dr. Banerjee’s lab for their suggestions and discussions. Additionally, I would like to thank my friends and family for their support. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ii LIST OF TABLES viii LIST OF FIGURES ix ABBREVIATIONS xi ABSTRACT xii CHAPTER I. Introduction:
    [Show full text]
  • Sattler Wsu 0251E 12373.Pdf (2.595Mb)
    STRUCTURAL AND MECHANISTIC CHARACTERIZATION OF ENZYMES IN PERSULFIDE OXIDATION AND MONOLIGNOL BIOSYNTHESIS PATHWAYS By STEVEN ANDREW SATTLER A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY WASHINGTON STATE UNIVERSITY School of Molecular Biosciences MAY 2018 © Copyright by STEVEN ANDREW SATTLER, 2018 All Rights Reserved © Copyright by STEVEN ANDREW SATTLER, 2018 All Rights Reserved To the Faculty of Washington State University: The members of the Committee appointed to examine the dissertation of STEVEN ANDREW SATTLER find it satisfactory and recommend that it be accepted. ChulHee Kang, Ph.D., Chair Susan Wang, Ph.D. Luying Xun, Ph.D. Margaret Black, Ph.D. ii ACKNOWLEDGMENT There are many people who I would like to thank for helping place me in a position to earn this degree. Foremost, I would like to thank my academic advisors, friends, and family for their guidance, support, and patience while I spent several years as an undergraduate and doctoral student. Most of my achievements are attributed to your respective influences on my education or disposition, and for that I will always be grateful. Even if you are not mentioned by name in this acknowledgment, know that your influence is appreciated. I would first like to thank my doctoral advisor, Dr. ChulHee Kang, for providing me with an opportunity to earn this degree. His guidance and willingness to listen to my ideas were crucial to my development as a scientist and prepared me for a professional career in theoretical work. I would also like to thank Dr. Luis Matos, who provided me with my first research opportunity as an undergraduate.
    [Show full text]
  • ETHE1 (B-12): Sc-393869
    SAN TA C RUZ BI OTEC HNOL OG Y, INC . ETHE1 (B-12): sc-393869 BACKGROUND APPLICATIONS ETHE1 (ethylmalonic encephalopathy 1), also known as HSCO (hepatoma sub - ETHE1 (B-12) is recommended for detection of ETHE1 of mouse, rat and tracted clone one protein), is a 254 amino acid protein belonging to the met - human origin by Western Blotting (starting dilution 1:100, dilution range allo- β-lactamase superfamily and glyoxalase II family. Localizing to the cyto - 1:100-1:1000), immunoprecipitation [1-2 µg per 100-500 µg of total protein plasm, nucleus and mitochondrion matrix, ETHE1 is ubiquitously expressed (1 ml of cell lysate)], immunofluorescence (starting dilution 1:50, dilution and may function in sulfide catabolism. ETHE1 binds two zinc ions per sub - range 1:50-1:500) and solid phase ELISA (starting dilution 1:30, dilution unit and interacts directly with RELA, preventing its localization to the nucle us range 1:30-1:3000). thus leading to suppressed p53-induced apoptosis. The gene encoding ETHE1 Suitable for use as control antibody for ETHE1 siRNA (h): sc-97755, ETHE1 maps to human chromosome 19q13.31. Mutations to this gene result in eth - siRNA (m): sc-144957, ETHE1 shRNA Plasmid (h): sc-97755-SH, ETHE1 ylmalonic encephalopathy, an infantile metabolic disorder characterized by shRNA Plasmid (m): sc-144957-SH, ETHE1 shRNA (h) Lentiviral Particles: high levels of ethylmalonic acid, neurodevelopmental delay and regression, sc-97755-V and ETHE1 shRNA (m) Lentiviral Particles: sc-144957-V. recurrent petechiae, acrocyanosis, and death within the first decade of life. Molecular Weight of ETHE1: 28 kDa.
    [Show full text]
  • Further Dissection of Qtls for Salt-Induced Stroke And
    www.nature.com/scientificreports OPEN Further dissection of QTLs for salt- induced stroke and identifcation of candidate genes in the stroke-prone Received: 2 February 2018 Accepted: 5 June 2018 spontaneously hypertensive rat Published: xx xx xxxx Kaoru Niiya1, Hiroki Ohara1, Masato Isono 3, Abdullah Md. Sheikh2, Hiroyuki Matsuo1, Koichi Fujikawa1, Minoru Isomura4, Norihiro Kato3 & Toru Nabika1 We previously revealed that two major quantitative trait loci (QTLs) for stroke latency of the stroke- prone spontaneously hypertensive rat (SHRSP) under salt-loading were located on chromosome (Chr) 1 and 18. Here, we attempted further dissection of the stroke-QTLs using multiple congenic strains between SHRSP and a stroke-resistant hypertensive rat (SHR). Cox hazard model among subcongenic strains harboring a chromosomal fragment of Chr-1 QTL region showed that the most promising region was a 2.1 Mbp fragment between D1Rat177 and D1Rat97. The QTL region on Chr 18 could not be narrowed down by the analysis, which may be due to multiple QTLs in this region. Nonsynonymous sequence variations were found in four genes (Cblc, Cxcl17, Cic, and Ceacam 19) on the 2.1 Mbp fragment of Chr-1 QTL by whole-genome sequence analysis of SHRSP/Izm and SHR/Izm. Signifcant changes in protein structure were predicted in CBL-C and CXCL17 using I-TASSER. Comprehensive gene expression analysis in the kidney with a cDNA microarray identifed three candidate genes (LOC102548695 (Zinc fnger protein 45-like, Zfp45L), Ethe1, and Cxcl17). In conclusion, we successfully narrowed down the QTL region on Chr 1, and identifed six candidate genes in this region.
    [Show full text]
  • Riboflavin Deficiency—Implications for General Human Health and Inborn
    International Journal of Molecular Sciences Review Riboflavin Deficiency—Implications for General Human Health and Inborn Errors of Metabolism 1, 1,2, 1 1 1 Signe Mosegaard y, Graziana Dipace y , Peter Bross , Jasper Carlsen , Niels Gregersen and Rikke Katrine Jentoft Olsen 1,* 1 Research Unit for Molecular Medicine, Department for Clinical Medicine, Aarhus University and Aarhus University Hospital, 8200 Aarhus N, Denmark; [email protected] (S.M.); [email protected] (G.D.); [email protected] (P.B.); [email protected] (J.C.); [email protected] (N.G.) 2 Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70121 Bari, Italy * Correspondence: [email protected]; Tel.: +45-78455412 These authors contributed equally to this work. y Received: 30 April 2020; Accepted: 26 May 2020; Published: 28 May 2020 Abstract: As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms.
    [Show full text]
  • The Response of Sulfur Dioxygenase to Sulfide in the Body Wall of Urechis Unincinctus
    The response of sulfur dioxygenase to sulfide in the body wall of Urechis unincinctus Litao Zhang1,2 and Zhifeng Zhang2 1 School of Biological Science, Jining Medical University, Rizhao, China 2 Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, China ABSTRACT Background. In some sedimentary environments, such as coastal intertidal and subtidal mudflats, sulfide levels can reach millimolar concentrations (2–5 mM) and can be toxic to marine species. Interestingly, some organisms have evolved biochemical strategies to overcome and tolerate high sulfide conditions, such as the echiuran worm, Urechis unicinctus. Mitochondrial sulfide oxidation is important for detoxification, in which sulfur dioxygenase (SDO) plays an indispensable role. Meanwhile, the body wall of the surface of the worm is in direct contact with sulfide. In our study, we chose the body wall to explore the SDO response to sulfide. Methods. Two sulfide treatment groups (50 mM and 150 mM) and a control group (natural seawater) were used. The worms, U. unicinctus, were collected from the intertidal flat of Yantai, China, and temporarily reared in aerated seawater for three days without feeding. Finally, sixty worms with similar length and mass were evenly assigned to the three groups. The worms were sampled at 0, 6, 24, 48 and 72 h after initiation of sulfide exposure. The body walls were excised, frozen in liquid nitrogen and stored at −80 ◦C for RNA and protein extraction. Real-time quantitative RT- PCR, enzyme-linked immunosorbent assay and specific activity detection were used to explore the SDO response to sulfide in the body wall.
    [Show full text]
  • Ethylmalonic Encephalopathy in an Indian Boy
    C A S E R E P O R T Ethylmalonic Encephalopathy in an Indian Boy SUNITA BIJARNIA-MAHAY, $DEEPTI GUPTA, *YOSUKE SHIGEMATSU, #SEIJI YAMAGUCHI, $RENU SAXENA AND IC VERMA From Institute of Medical Genetics & Genomics and $Department of Molecular Genetics, Sir Ganga Ram Hospital, New Delhi, India; *Department of Health Science, University of Fukui, Japan; and #Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan. Correspondence to: Dr Sunita Bijarnia- Background: Ethylmalonic encephalopathy is a rare inborn error of metabolism Mahay, Senior Consultant and Associate characterized by neurodevelopmental delay / regression, recurrent petechiae, orthostatic Professor, GRIPMER, Institute of Medical acrocyanosis, and chronic diarrhea. Case Characteristics: 4-year-old boy with Genetics & Genomics, Sir Ganga Ram developmental regression, chronic diarrhea, petechial spots and acrocyanosis. MRI brain Hospital, Rajinder Nagar, New Delhi 110 showed T2W/FLAIR hyperintensities in bilateral caudate and putamen. Abnormal acyl- 060, India. [email protected] carnitine profile and metabolites on urinary GC-MS analysis suggested the diagnosis. Received: October 28, 2015; Intervention: Sequencing of ETHE1 gene revealed mutations: c.488G>A and c.375+5G>T Initial review: March 04, 2016; (novel). Message: EE is clinically-recognizable disorder with typical clinical features. Accepted: May 13, 2016. Keywords: Inborn error of metabolism, Neuroregression, ETHE1 gene. thylmalonic encephalopathy (EE) is a rare After two years of age, parents noted loss of inborn error of metabolism affecting brain, milestones. He was speaking less than before and stopped peripheral blood vessels and gastrointestinal sitting without support. The hypotonia in infancy Etract, with devastating consequences. Caused gradually gave way to spasticity after 2 years of age by recessive mutations in ETHE1 gene, it is characterized which was progressive in nature.
    [Show full text]